The present invention relates to a mouse model with natural onset of morbid conditions strikingly similar to those of rheumatoid arthritis developing in humans. This strain of mice is useful as an animal model of rheumatoid arthritis.
Among autoimmune diseases, rheumatoid arthritis is the most frequent disease; for example, the number of patients with this disease in the US is estimated to be 6.5 millions. The cause and pathogenetic mechanism of this disease are largely unknown at present.
For elucidation of the cause and mechanism of diseases of unknown etiology, animal models are useful, especially when they naturally develop the diseases clinically and pathologically similar to the human counterparts. For example, the NOD strain of mice develop insulin-dependent diabetes mellitus, which is an autoimmune disease like rheumatoid arthritis (Makino, S. et al. Exp. Animals (Tokyo) 29, 1-13, 1980). NZB and NZW mice are used widely as a model for systemic lupus erythematosus (SLE) (Andrews, B. S. et al., J. Exp. Med. 148, 1198-1215, 1978). These animals have greatly contributed to the elucidation of the cause and mechanism of respective diseases.
Some animals showing similar morbid conditions to those of rheumatoid arthritis in humans are also known. For example, MRLlpr/lpr mice show natural onset of arthritis mainly in the leg joints (Hang, L. et al., J. Exp. Med. 155:1690, 1982). However, the arthritis in this strain is generally mild, and the maintenance of the strain for a prolonged period is difficult because of abnormal proliferation of lymphocytes in the lymph nodes and spleen, hampering the wide use of the strain as a model of arthritis. Collagen arthritis can be induced in mice by immunizing with type II collagen, which is abundant in joints, along with strong adjuvant (Stuart, J. M. et al., Annual Rev. Immunol. 2;199, 1984). Adjuvant arthritis can also be induced in rats by immunizing with dead tubercule bacilli (Taurog, J. D. et Mu al., Cell Immunol. 75:271, 1983). Although these models show morbid conditions similar to those of rheumatoid arthritis, the relationship of human rheumatoid arthritis to the abnormality of type II collagen or to the infection with tubercule bacilli is not proven. Accordingly, the findings obtained by utilizing these model animals cannot necessarily be extrapolated to humans, and it is contenions whether these animals can be used as suitable models of human rheumatoid arthritis.
PROBLEM TO BE SOLVED BY THE INVENTION
An animal model with immunopathological characteristics of rheumatoid arthritis, is necessary for development of effective therapies for rheumatoid arthritis in humans. The present invention meets such a requirement, and the object of the invention is to provide a mouse model with natural onset of morbid conditions strikingly similar to those of rheumatoid arthritis in humans.
A deposit of the SKG strain has been made with and accepted by the International Patent Organism Depositary, National Institute of Advanced Industrial Science and Technology, located at AIST Tsukuba Central 6, 1-1, Higashi 1-Chome, Tsukuba-shi, Ibaraki-ken 305-8566, Japan, on Nov. 6, 2001. The Accession Number is FERM BP-7790.
As a result of his extensive study for solving the problems described above, the present inventor found a mouse with joint swelling among a normal BALB/c colony, and from this finding, attained the present invention. Hence, the present invention is a mouse strain having the character of natural onset of autoimmune arthritis. This mouse strain was designated as the SKG strain.
Hereinafter, the present invention is described in detail.
The mouse of the invention, which was designated as the SKG strain, possesses the character of natural onset of autoimmune arthritis. Although the time of onset of autoimmune arthritis varies among individual mice, the onset of the arthritis is usually about 3 to 4 months after birth. As described in the xe2x80x9cBACKGROUND ARTxe2x80x9d above, MRL-lpr/lpr mice also show natural onset of arthritis. However, the mouse of the invention and the MRL strain are different in their morbid conditions. For example, the arthritis in the MRL strain is generally localized to the joints of the hind legs, and even after progressing chronically, does not lead to joint stiffening, while the arthritis in the mouse of the invention develops in the joints of the forelegs and hind legs, and chronically progressing to joint stiffening. Furthermore, the mouse of the invention does not show the abnormal proliferation of lymphocytes or the SLE-like lesions observed in the MRL strain.
The autoimmune arthritis observed in the mouse of the invention is strikingly similar to human rheumatoid arthritis in morbid conditions. Specifically, there are the following similarities therebetween:
1) It pathohistologically resembles human rheumatoid arthritis in its chronic progression from the appearance of pannus to the inflammatory destruction of joint cartilage and bone accompanied by lymphocyte infiltration (FIGS. 9 and 11).
2) Clinically, it resembles human rheumatoid arthritis in that the small and large joints of the forelegs and hind legs are affected symmetrically, and in that the lesions chronically progress and finally lead to joint stiffening (FIGS. 1, 3, 5 and 7).
3) It resembles human rheumatoid arthritis in that rheumatoid factor, autoantibody against type II collagen specific for joints, and hypergammaglobulinemia develops highly frequently in the mouse of invention (FIGS. 14, 15 and 16).
From these similarities, the mouse of the invention can be used as a good model of human rheumatoid arthritis. The mouse of the invention can be produced by mating between SKG strain of mice or by mating them with other suitable strains of mice and selecting the obtained mice for those having the characters described above. The applicant will distribute the SKG strain of mice in accordance with the stipulation of Article 27-3, Item 1, of the Japanese Patent Law Enforcement Regulations.